The G-protein coupled receptor (GPCR) family is the largest known gene family representing greater than 1% of the human genome, and encompassing a wide range of biological functions (including various autocrine, paracrine and endocrine processes). The GPCR superfamily is also the most exploited gene family by the pharmaceutical industry for the development of therapeutic compounds. GPCRs have been categorized into rhodopsin-like GPCRs, the secretin-like GPCRs, the cAMP receptors, the fungal mating pheromone receptors, and the metabotropic glutamate receptor family. The rhodopsin-like GPCRs themselves represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of rhodopsin-like GPCRs are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) spanning a-helices and are coupled to G-proteins within the cell which dissociate from the receptor on agonist binding and initiate or inhibit secondary messenger signalling mechanisms. See: Lander et al. Nature 409:860 (2001); Basic and clinical pharmacology, 8th Ed., Katzung. USA: The McGraw Hill Companies, Inc. (2001).
The rhodopsin-like GPCR family includes several classes of receptors which are variously distributed throughout the central nervous system (CNS) and many peripheral sites and have been implicated in a variety of CNS and neuropsychiatric conditions. Included among these receptors are dopamine (“D”) receptors, and 6 of 7 main subtypes of serotonin (5-hydroxytryptamine, “5HT”) receptors (5HT1, 2 and 4-7 receptor subtypes are GPCRs while the 5HT3 receptor subtypes are ligand-gated Na+/K+ ion channel).
Dopamine neurons in the vertebrate central nervous system are involved in the initiation and execution of movement, the maintenance of emotional stability, and the regulation of pituitary function. Dopamine binding to the extracellular binding groove of D receptors activates G-proteins—the D1 and D5 receptor subtypes (“D1-like”) are linked to stimulatory G-proteins, whereas receptor subtypes 2-4 (“D2-like”) are linked to inhibitory G-proteins. D2-like receptors are found through out the brain and in smooth muscle and presynaptic nerve terminals and have an inhibitory effect on neurotransmission when bound by an agonist. Specifically, D2 receptors are abundant and widespread in the striatum, limbic system, thalamus, hypothalamus, and pituitary gland). Antagonist binding to D2 receptors inhibits agonist binding and therefore prevents the inhibition of down-stream signalling mechanisms. Antagonists of D2 receptors are used in the treatment of psychoses (e.g., schizophrenia, mania, psychotic depression, and bipolar disorder), and show utility for short-term sedation in aggression or agitation (e.g., amisulpride, clozapine, haloperidol, nemonapride, pimozide, remoxipride, spiperone, sulpiride) and may be useful for treating drug addicion, while agonists of D2 receptors are used in the treatment of Parkinson's disease and to suppress prolactin secretion arising from tumours of the pituitary gland (e.g., apomorphine, bromocriptine, dihydroergotamine, piribedil, quinpirole), and to treat restless legs syndrome (RLS; e.g., pramipexole, ropinirole). See: Basic and clinical pharmacology, 8th Ed., Katzung. USA: The McGraw Hill Companies, Inc. (2001); Pharmacology, 4th Ed., Rang et al. Edinburgh, UK: Harcourt Publishers Ltd. (2001); Sedvall et al. The Lancet, 346:743-749, (1995); Hietala. The Lancet, 346:1130-1131 (1995); Kemppainen et al. Eur J Neurosci., 18:149-154 (2003)
5-Hydroxytryptamine is ubiquitous in plants and animals. It is an important neurotransmitter and local hormone in the CNS and intestine, and is implicated in a vast array of physiological and pathophysiological pathways. 5-Hydroxytriptamine binding to the extracellular binding groove of 5HT receptors activates G-proteins—the 5HT1 receptor subtypes are known to be linked to inhibitory G-proteins, whereas subtypes 2, 4, 6 and 7 are known to be linked to stimulatory G-proteins. Of these, 5HT1 receptor subtypes (at least 5 are known) are known to occur primarily in the brain and cerebral blood vessels where they mediate neural inhibition and vasoconstriction. Specific agonists at 5HT1 receptors are used in migraine therapy (e.g., sumatriptan) and in the treatment of stress/anxiety (e.g., buspirone), while antagonists have been recommended in the treatment of psychoses (e.g., spiperone, methiothepin). Additionally, regulation of the 5HT1 receptor subtypes have been implicated in drug addiction, Alzheimer's disease, Parkinson's disease, depression, emesis, and eating disorders. 5HT2 receptor subtypes (at least 3 are known) are found throughout the CNS and at many peripheral sites where they produce excitatory neuronal and smooth muscle effects. 5HT2 receptor antagonists are employed in migraine therapy (e.g., methisergide) and have shown potential in the treatment of scleroderma and Raynaud's phenomenon (e.g., ketanserin). 5HT3 receptors are known to occur mainly in the peripheral nervous system and antagonists are employed as anti-emetics (e.g., ondansetron, tropisetron). 5HT4 receptors are found in the brain, as well as the heart, bladder and gastrointestinal (GI) tract. Within the GI tract they produce neuronal excitation and mediate the effect of 5HT in stimulating peristalsis. Specific 5HT4 receptor antagonists are used for treating GI disorders (e.g., metoclopramide). 5HT receptor subtypes 5 (at least 5 are known), 6, and 7 are also found throughout the CNS and may be potential targets for small-molecule drugs. In particular, the 5HT7 receptor subtype has been implicated in depression, psychoses, Parkinson's disease, Alzheimer's disease, Huntington's disease, migraine, stress/anxiety, eating disorders, and emesis. See: Basic and clinical pharmacology, 8th Ed., Katzung. USA: The McGraw Hill Companies, Inc. (2001); Pharmacology, 4th Ed., Rang et al. Edinburgh, UK: Harcourt Publishers Ltd. (2001); Kleven et al. European Journal of Pharmacology, 281:219-228 (1995); U.S. Pat. No. 5,162,375; Leone et al. Neuro Report, 9:2605-2608(1998); U.S. Pat. No. 4,771,053; WO 01/52855; De Vry et al. European Journal of Pharmacology, 357:1-8 (1998); Wolff et al. European Journal of Pharmacology, 340:217-220 (1997); Alfieri et al. British Journal of Cancer, 72:1013-1015 (1995); Wolff et al., Pharmacology Biochemistry and Behavior, 52:571-575 (1995); Lucot. European Journal of Pharmacology, 253:53-60 (1997); U.S. Pat. Nos. 5,824,680; 4,687,772; Rasmussen et al. Annual Reports in Medicinal Chemistry, 30:1-9 (1995); WO 00/16777; U.S. Pat. No. 4,438,119; Millan, Journal of Pharmacology and Experimental Therapeutics, 295:853-861 (2000); WO 93/04681; Miyamoto, et al. Current Opinion in CPNS Investigational Drugs, 2:25 (2000); Hagger, et al. Biol. Psychiatry, 34:702 (1993); Sharma et al. J. Clin. Psychopharmacol., 18:128 (1998); Lee et al. J. Clin. Psychiatry, 55:82 (1994); Fujii, et al. J. Neuropsychiatry Clin. Neurosci., 9:240 (1997); Mason et al. Eur. J. Pharmacol., 221:397 (1992); Newman-Tancredi et al. Neuropharmacology, 35:119, (1996); Sumiyoshi et al. J. Clin. Pharmacol., 20:386 (2000); Carli et al. Eur. J. Neurosci., 10:221 (1998); Meneses et al. Neurobiol. Learn. Mem., 71:207 (1999); and Glennon et al. Neuroscience and Behavioral Reviews, 14:3547 (1990).
The action of 5HT at synapses is terminated by its Na+/K+-mediated reuptake across the pre-synaptic membrane. 5HT-reuptake inhibitors are employed in the treatment of depression, stress/anxiety, panic disorder, obsessive compulsive disorder, eating disorders, and social phobias, (e.g., citalopram, clomipramine, fluoxetine, fluvoxamine, indatraline, zimelidine) and may be useful in the treatment of migraine, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's disease, drug addiction, eating disorders, scleroderma and Raynauds phenomenon, GI tract disorders related to the regulation of peristalsis, and/or emesis. See: Basic and clinical pharmacology, 8th Ed., Katzung. USA: The McGraw Hill Companies, Inc. (2001); Pharmacology, 4th Ed., Rang et al. Edinburgh, UK: Harcourt Publishers Ltd. (2001); Masson et al. Pharm. Rev. 51:439 (1999); and additionally, the references in the preceding paragraphs.
Accordingly, it would be desirable to provide compounds which modulate GPCRs in a form suitable for administration to a patient in need of treatment for any of the above-mentioned disorders. In particular, it would be desirable for such compounds to exhibit additional characteristics such as good solubility, stability and ease of formulation, etc.